Oral systemic administration of drugs, in general, is the preferred mode of administration in ambulatory treatment regimens which require repetitive drug administration over periods of time. While oral systemic administration is very effective with respect to water soluble drugs, it proves to be a problematic administration route for hydrophobic drugs or drugs with limited aqueous solubility such as physostigmine base, isradipine, virginiamycine, cyclosporin A, morphin, buprenorphine, nalorphine, methorfan, probucol and others.
The poor systemic effect achieved with orally-administered hydrophobic drugs results from a number of factors. For one, hydrophobic drugs do not dissolve in water and form a separate phase in aqueous solutions and are thus not readily available for absorption through the walls of the GI tract. Furthermore, some hydrophobic drugs, which are absorbed primarily through the walls of the small intestine, particularly through the jejunum, may undergo a so-called "first pass effect", i.e passage of the drugs in the liver prior to reaching the blood system. The overall effect of these factors is that only low, often non effective, amounts of orally administered hydrophobic drugs eventually reach the target organ(s), i.e orally administered hydrophobic drugs have generally a low bioavailability. This may be overcome by increasing the dose of the drug, but such an increase may, however, result in increased incidence of side-effects owing to erratic and variable inter subject absorption.
There have been various proposals for increasing bioavailability of hydrophobic drugs. For example, previous studies using oleic acid containing a dissolved lipophilic drug, have demonstrated a beneficial effect on drug bioavailability (Stella et al, 1978, J. Pharm. Sci, 67, 1375-1377). Recently, it was shown that the bioavailability of propranolol following oral administration, can be improved by dissolving the drug in a lipid formulation containing mainly oleic acid and packing it into a sealed and entero-coated hard gelatine capsule (Barnwell et al, 1992, Int. J. Pharmaceutics, 88, 423-432).
Emulsions have been proposed as carriers in oral formulations of hydrophobic drugs in general (Pal et al, 1984, J. Int. Pharm, 33. 99-104; Myers et al, 1992, Int. J. Pharm. 78, 217-226) and for drugs such as physostigmine in particular (Rubinstein et al, 1991, J. Pharm. Res, 80, 643-647; Friedman et al, 1989, Drug Design and Delivery, 4, 135-142; Benita et al, 1989, Drug Delivery Design, 4, 143-153). Colloid particles of the emulsion which carry the drug are absorbed in the jejunum and are presumably carried away mainly by the lymph through the thoracic duct, thus bypassing the liver and greatly reducing the first pass effect. Indeed, the oral bioavailability of several lipophilic drugs was shown to be somewhat improved using emulsions as vehicles for their oral systemic administration.
However, in many cases emulsion formulations offered no improvement in the bioavailability of hydrophobic drugs versus their administration in aqueous formulations. This is particularly the case with respect to drugs such as physostigmine, which is an amphiphilic drug that localizes in the emulsion in the oil/water (o/w) interfacial film of the emulsion colloid particles. During passage of an emulsion containing physostigmine through the digestive tract, the emulsion, which is practically infinitely diluted, quickly releases the drug contained therein. This problem is increasingly augmented by the very strong acidity in the stomach which has a tendency to reduce the stability of the emulsion's colloid particles.
Certain lipid solutions, by virtue of their ingredients, have the capacity to undergo spontaneous emulsification when introduced into an aqueous phase following gentle agitation yielding oil-in-water emulsions. Such lipid solutions are defined in the literature as self-emulsifying delivery systems (Charman et al, 1992, Pharm. Res, 9, 87-93). Self-emulsifying delivery systems have been formulated using medium-chain triglyceride oils and nonionic surfactants which, depending on their exact nature, could form the basis of a self-emulsifying drug delivery system (Pouton, 1985a, Int. J. Pharm. 27, 335-348; Pouton 1985b, Int. J. Pharm. 37, 1P; Pouton et al, 1987, Proc. Int. Symp. Control. Rel. Bioacta. Mater, 14, 113-117; Wakerly et al, 1986, ACS. Symp. Ser. 311, 242-255; Wakerly et al, 1987, J. Pharm. Sci, 67, 1375-1377). These formulations may be encapsulated in soft gelatine capsules or sealed hard gelatin capsules to yield precise and convenient unit dosage systems.
Early studies in the small intestine clearly established, that the absorptive cell interior is negative with respect to mucosal solution (Csaky, Ill. (Ed.), Handbook of Experimental Pharmacology, Vol 70, Springer-Verloy, Berlin, (1984), 324-325). It has also been reported that some hydrophobic cationic drugs, completely ionized over the pH range of the GI tract, are absorbed rapidly, in spite of their poor water solubility (Iseky, K, Hirano, T, Fukushi, Y, Kitamura, Y, Miyazaki, S, Takada, M; Sugawara, M, Saiton, H and Miyazaki, K. (1992), J. Pharm. Pharmacol, 44:9, 722-726; Saiton, H, Kawai, S, Iseki, K, Myazaki, K and Arita, T. (1988), J. Pharm. Pharmacol, 41, 200-202). Moreover, some endogenic compounds bind to endothelial surfaces by its NH2-terminal, indicating physiological importance of the electrostatic interactions (21).
The formation of oily droplets containing a dissolved drug brings about distribution of the drug throughout the GI tract while providing a large interfacial area for partitioning of the drug between the oil and the surrounding aqueous phase. Thus, for drugs with limited aqueous solubility, which are poorly absorbed in the GI tract, the spontaneous disintegration of the lipid phase into very fine dispersed oily droplets may offer an improvement in both the rate and extent of absorption. All the self-emulsifying drug delivery systems known to date, contain large concentrations of surfactants (up to 50%) which were either non-ionic (such as Tween.sup.(R), Span.sup.(R)) or anionic surfactants (such as phospholipids) resulting in the formation of oily droplets having either a neutral or an electronegative charge.
In a recent report (Elbaz et al, 1993, Int. J. Pharm. 96, R1-R6) an emulsified drug delivery system has been disclosed in which the colloid particles bear a positive charge. However, no mention was made in this publication to the possibility of using such emulsions as an oral systemic drug delivery vehicle.
It is an object of the present invention toprovide a self-emulsifying formulation useful as a drug delivery system of lipophilic drugs.
It is a further object of the invention to provide a novel drug delivery system for the systemic oral administration of lipophilic drugs.
It is yet another object of the invention to provide a novel method for the administration of lipophilic drugs.
It is yet still a further object of the invention to provide a method for production of an emulsion by the use of a self-emulsifying oily preparation.